Overweight and obesity are growing problems worldwide. Obesity is a tremendous health burden for the U.S. with estimates of >10% of health care expenditures devoted annually to the problem, due to morbidity from its associated conditions. Moreover, this is an alarming issue in the Pediatrics population. A recent estimate indicates that 15.5% of American children currently overweight or obese, doubling in the past 2 decades, with even higher rates among minority and economically disadvantaged groups. While socioeconomic and cultural factors clearly play an important role, the genetics of obesity is now being dissected and several genes are now implicated in the susceptibility to this disorder. Understanding mechanisms by which these genes exert their effects on body fat composition may provide important clues that will aid in developing new strategies to aid in the war on obesity and its co-morbid conditions. Growth differentiation factor 3 (Gdf3) is a member of the TGF-b superfamily, expressed in adipose. We have generated mice with a homozygous null mutation of this gene. When maintained on a high fat diet, these knockout mice exhibit resistance to obesity, suggesting a possible role in adipocyte differentiation and/or function. This proposal aims to study this phenomenon further, potentially leading to pharmacologic interventions to help combat this disease. The specific aims of this proposal are 1) to further define which cell types within white adipose tissue express GDF3 2) to assess the physiologic and molecular contributors to the increased metabolic rates of Gdf3-/- mice 3) to further examine GDFS's roles in the mature adipocyte. [unreadable] [unreadable] [unreadable] [unreadable]